WO1999063990A1

WO1999063990A1 - New use

Info

Publication number: WO1999063990A1
Application number: PCT/SE1999/001033
Authority: WO
Inventors: Bengt ÅBLAD
Original assignee: Astrazeneca Ab
Priority date: 1998-06-11
Filing date: 1999-06-10
Publication date: 1999-12-16
Also published as: SE9802075D0; AU4812199A

Abstract

There is provided the use of a NPY-antagonist for the manufacture of a medicament for the treatment of peptic ulcer disease, or of multiple organ failure.

Description

NEW USE

Field of the Invention

This invention relates to a new use of NPY antagonists.

Background of the invention

NPY Antagonists

Neuropeptide Y (NPY) is a peptide consisting of 36 amino acids. In recent years it has been established that NPY is an important co-transmitter in the peripheral sympathetic nerve system.

Released NPY is known to elicit marked constriction of blood vessels both in the heart and in most peripheral organs. This vasoconstrictive effect of NPY is believed to be mainly mediated by a receptor sub-type known as Y, . Released NPY may also act on autonomic nerve endings to inhibit the release of neurotransmitters, which may thereby reduce the cardiac vagal tone. This effect of NPY is believed to be mediated by a receptor sub-type known as Y₂.

Other NPY receptor sub-types have been identified, namely the Y₃, Y₄, Y₅ and Y₆ sub-types. The precise function of these sub-receptors has not been elucidated in any detail, but it has been widely postulated that the Y₅ subtype is involved in the regulation of feeding and eating (see, for example, Exp. Opin. Invest. Drugs, vol. 6, pp. 437-445 (1997)). Antagonists of NPY have been indicated as being of potential use in the treatment of many different conditions, including cardiovascular diseases such as hypertension, myocardial ischaemia, myocardial infarction, cardiac failure, vasospasm and arrhythmia, as well as in the treatment of kidney failure, cerebral haemorrhage, pain, migraine, anxiety, depression, ώflammation, Alzheimer's disease, asthma, epilepsy, diabetes, sleeping disorders, obesity and eating disorders.

Dyspepsia is a very common medical condition. It has been estimated that up to 40% of the western population experience dyspeptic symptoms, many of which result from peptic ulcer disease.

The symptoms of dyspepsia due to peptic ulcers or ulcer-like conditions can be treated by administration of antacids and inhibitors of gastric secretion (e.g. H₂-antagonists and proton pump inhibitors). Treatments which involve the employment of antacids are, however, short lasting, and such drugs must be administered repeatedly during the day. Inhibitors of gastric secretion have the disadvantage that they are expensive and may have an impact on gut physiology, thus increasing the risk of intestinal and/or systemic infections.

Prokinetic drugs (e.g. cisapride), and anticholinergic compounds, are often administered for the treatment of dyspeptic symptoms, usually with variable effect and high incidence of side effects.

Haemorrhage and/or trauma elicit a vasoconstrictive response that preferentially reduces blood flow to mesenteric organs. If severe, haemorrhage may result in circulatory shock, a condition in which oxygen delivery becomes insufficient to maintain tissue integrity and function. Manifestations of circulatory shock on mesenteric organs include collapse of the gut permeability barrier, which enables gut pathogens to cross the intestinal mucosa and eventually spread to systemic compartments via lymphatic or blood vessels. The barrier dysfunction with microbial translocation, together with the initially comprised systemic circulation, leads to disruption of haemostasis and functional failure of various organ systems (kidneys, heart, lungs, etc.). Such a sequential development of devastating sequels is defined as multiple organ failure (MOF).

The treatment of MOF is very costly and results in long term treatment in intensive care units. Therapeutic efforts in MOF treatment today, are aimed at life-sustaining treatments such as antibiotics, volume expansion and respiration assistance. However, a therapeutic approach to the maintenance of mesenteric blood flow and oxygen delivery is not available at present.

Prior art

Known NPY antagonists, including benextramine, CC2137, arpromidine, BIBP3226, NGD 95-1, SR120819A, SR120107A, 1229U91 and PD160170, are described in DDT, vol. 2 pages 19-24 (1997), which provides a general review of patents and patent applications in the NPY area.

A general review of NPY antagonists is also provided in Peptides vol. 18, No. 3, pages 445-57 (1997).

Non-peptide based (which term includes amino acid-based) antagonists of NPY have been disclosed in European patent applications EP 614 911, EP 747 357, EP 747 356 and EP 747 378; international patent applications

WO 94/17035, WO 97/19911 , WO 97/19913, WO 96/12489, WO

97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308,

WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041 , WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos. 5,552,411 , 5,663,192 and 5,567,714; and Japanese patent application JP 09157253, as well as in international patent application WO 99/15498 (the latter application includes full details of the synthesis of various novel NPY antagonists, including (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxy- phenyl)ethyl]arginine amide).

European patent application EP 614 911 (which discloses sulphamoyl substituted derivatives of phenylalanine amidine) and international patent application WO 94/17035, do not mention the receptor sub-type upon which the disclosed compounds act.

European applications EP 747 357, EP 747 356 and EP 747 378 disclose dihydropyridine derivatives as sub-receptor Y, antagonists.

International patent applications WO 96/12489, WO 96/12490, WO 97/09308, WO 97/25041 and US patents Nos. 5,567,714 and 5,663,192 disclose benzothiophene, benzimidazole and indole derivatives as sub-receptor Y, antagonists.

International patent applications WO 96/40660, WO 98/03492, WO 98/03493 and WO 98/03494 disclose benzylamine derivatives as sub-receptor Y, antagonists and/or partial sub-receptor Y, agonists. US patent No. 5,552,411 discloses quinoline derivatives as sub-receptor

Y, antagonists.

International patent applications WO 97/34872 and WO 98/07420 disclose 2,4-diaminopyridines and mono- or disubstituted ureas respectively.

Japanese patent application JP 09157253 discloses amino acid derivatives as NPY antagonists.

International patent applications WO 97/19682, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823 and WO 97/46250 disclose arylsulfonamide and quinazoline derivatives as sub-receptor Y₅ antagonists and thus for use in the treatment of eating disorders.

The compounds disclosed in international patent application WO 96/22305 are described as having Y₂ sub-receptor antagonist activity and are indicated for use in the treatment of eating disorders. Amongst the compounds specifically disclosed are phenylalanine amide derivatives of N-(diphenylpropionyl)arginine .

International patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 97/19914 and WO 99/15498 disclose certain amino acid derivatives as antagonists of NPY. WO 94/17035 discloses BIBP3226.

Peptide derivatives as NPY antagonists are disclosed in international patent applications WO 94/00486, WO 93/12139, WO 95/00161, US Patent No. 5,328,899, German patent application DE 393 97 97, European patent applications EP 355 794 and EP 355 793 and Japanese patent applications JP 06116284 and JP 07267988. None of the aforementioned prior art documents mention or suggest that the NPY antagonists disclosed therein may be useful in the treatment of peptic ulcer diseases, or of MOF.

Disclosure of the Invention

Surprisingly, we have found that NPY antagonists reduce vascular constriction in the gastrointestinal tract, and may thus be used to reduce the symptoms of, and to treat, peptic ulcer disease, as well as MOF (for example, as demonstrated in the Examples described below).

According to the invention there is provided the use of a NPY antagonist for the manufacture of a medicament for the treatment of peptic ulcer disease, or of MOF.

We have found that NPY antagonists may be used to treat such conditions in preferably mammalian, and especially human, patients.

The term "peptic ulcer disease" will be understood to include all classes of peptic ulcer (i.e. ulceration of the mucous membrane of a relevant part of the gastrointestinal tract, e.g. the oesophagus, stomach, duodenum, etc.) as well as the symptoms which are associated with such a condition, such as pain and dyspepsia (i.e. impairment of the power or function of digestion in the gastrointestinal tract, before, during or after the intake of food or drink).

The term "MOF" stands for "multiple organ failure" and will be understood to include the sequence of events referred to hereinbefore. The term "NPY antagonist" will be well understood by those skilled in the art to include all those compounds which inhibit the activity of NPY to an experimentally determinable degree, i.e. those compounds which bind to a NPY receptor without eliciting a biological response, for example those compounds which, by binding to NPY receptors, inhibit the functional activity of NPY with an IC₅₀ (as measured in, for example, rat-brain cortex membranes) of less than 10 μM. The term thus includes antagonists of all NPY receptor sub-types including the Y_{l 5} Y₂, Y₃, Y₄, Y₅ and Y₆ sub-types. However, we prefer that the NPY antagonist is a NPY Y, sub-receptor antagonist.

NPY antagonists which may be mentioned include those disclosed in European patent applications EP 614 911, EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos. 5,552,411, 5,663,192 and 5,567,714; Japanese patent application JP 09157253; international patent applications WO 94/00486, WO 93/12139, WO 95/00161 and WO 99/15498; US Patent No. 5,328,899; German patent application DE 393 97 97; European patent applications EP 355 794 and EP 355 793; and Japanese patent applications JP 06116284 and JP 07267988, the disclosures in all of which documents are hereby incorporated by reference. Preferred NPY antagonists include those compounds that are specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide-based NPY antagonists. Amino acid and non-peptide-based NPY antagonists which may be mentioned include those disclosed in European patent applications EP 614 911 , EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041 , WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; US patents Nos. 5,552,411 , 5,663, 192 and 5,567,714; and Japanese patent application JP 09157253. Preferred amino acid and non-peptide-based NPY antagonists include those compounds that are specifically disclosed in these patent documents.

Particularly preferred compounds include amino acid-based NPY antagonists. Amino acid-based compounds which may be mentioned include those disclosed in international patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 97/19914 or, preferably, WO 99/15498. Preferred amino acid-based NPY antagonists include those that are specifically disclosed in these patent documents, for example BIBP3226 and, especially, (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxy- phenyl)ethyl]arginine amide (Example 4 of international patent application WO 99/15498).

Pharmaceutical Preparations

In accordance with the invention, the NPY antagonists may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the active ingredient either as a free base, or a pharmaceutical acceptable non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending on the disorder, and the patient, to be treated, as well as the route of administration, the compositions may be administered at varying doses (see below) .

In the therapeutic treatment of mammals, and especially humans, the NPY antagonists may be given as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The preparation of suitable formulations for use in administering NPY antagonists is described in the literature, including European patent applications EP 614 911 , EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos. 5,552,411 , 5,663,192 and 5,567,714; Japanese patent application JP 09157253; international patent applications WO 94/00486, WO 93/12139, WO 95/00161 and WO 99/15498; US Patent No. 5,328,899; German patent application DE 393 97 97; European patent applications EP 355 794 and EP 355 793; and Japanese patent applications JP 06116284 and JP 07267988, the disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations will be well known to those skilled in the art. Combinations of NPY antagonists may be used.

The amounts of NPY antagonist in the formulation will depend on the condition, and patient, to be treated, as well as the compound(s) which is/are employed.

According to a further aspect of the invention there is provided a pharmaceutical formulation for use in the treatment of peptic ulcer disease, or of MOF, comprising an effective amount of a NPY antagonist and a pharmaceutically-acceptable adjuvant, diluent or carrier.

The NPY antagonists may also be combined with other therapeutic agents that are useful in the treatment of peptic ulcer disease (e.g. antacids, proton pump inhibitors, etc.), or of MOF (e.g. angiotensin II antagonists, volume supplementation, dopaminergic agents, vasodilators, etc).

Suitable doses of the NPY antagonists in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients are 0.01 to 10 mg/kg body weight per day at peroral administration and 0.001 to 1.0 mg/kg body weight per minute at parenteral administration.

According to a further aspect of the invention there is provided a method of treatment of peptic ulcer disease, or of MOF, which comprises administering a therapeutically effective amount of a NPY antagonist to a patient in need of such treatment.

For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the prophylaxis, of a condition. The use and method described herein may have the advantage that, in the treatment of peptic ulcer disease, or of MOF, NPY antagonists do not possess the disadvantages of known drugs presently used in the treatment of such indications, such as those discussed hereinbefore.

The invention is illustrated, but in no way limited, by the following Examples.

Example 1

The effect of NPY antagonists on MOF in pigs was evaluated as follows.

Anaesthetised pigs were exposed to haemorrhage by withdrawal of blood (25 mL/kg body weight, corresponding to about 30% of the total blood volume) for 30 minutes. The haemodynamic and metabolic consequences in the intestines were studied by recording arterial pressure, portal vein blood flow, pH and oxygen saturation in arterial and portal venous blood before and after bleeding. Basal values were recorded for one hour (0 to 60 minutes). Following this, blood was withdrawn for 30 minutes (60 to 90 minutes) and the responses to bleeding were recorded for the next 40 minutes (90 to 130 minutes).

More specifically, four male pigs were studied. Two of these were given

2 the NPY_rantagonist (_.)-N -(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)- ethyl] arginine amide (Compound I, disclosed in international patent application WO 99/15498 as Example 4) by i.v. infusion in a dose of 0.06 μmol/kg per minute during the experimental time 20 to 140 minutes. The other two pigs were given a corresponding infusion of the vehicle. The two pigs given Compound I were still surviving after 140 minutes. The two pigs given control vehicle, however, died due to severe hypotension, one at 109 minutes, the other at 133 minutes.

The results obtained are tabulated below, at the following times: 20 minutes (before start of drug/vehicle infusion), 60 minutes (before start of bleeding), 90 minutes (at end of bleeding) and 130 minutes (40 minutes after end of bleeding). The results are given as means of the two drug and the two control experiments respectively.

Time (mins): 20 60 90 130

Arterial Blood Pressure (rnmHg)

Compound I 137 141 83 87

Control 135 143 69 22*

Portal Vein Flow (mL/s) Compound I 20.5 20.0 10.3 13.0

Control 13.7 15.7 5.3 3.1 *

pH in Portal Vein

Compound I 7.40 7.40 7.23 7.10

Control 7.40 7.41 7.08 6.59*

Oxygen supply (mL/s)

Compound I 92.7 79.4 93.9 108.5

Control 82.2 77.7 66.2 25.9*

*One animal died at 109 minutes It can be observed that, in the control pigs, the bleeding resulted in reductions of arterial pressure, of portal blood flow, pH, and oxygen supply, especially in portal venous blood. All these effects of the bleeding were significantly less pronounced in the pigs which were administered Compound I. The bleeding in control pigs led to increased (maximally 7- fold) intestinal vascular resistance (more marked reduction of portal blood flow than of arterial perfusion pressure). A corresponding vasoconstrictor response was absent in the pigs given compound I.

The results indicate that NPY antagonists (especially Y, sub-receptor antagonists) are likely to be of great value in the treatment of MOF.

Example 2

The effect of NPY antagonists on stress induced ulcers in the rat was evaluated as follows.

Two groups of 8 WISTSAR rats (control group, dosed intravenously with vehicle of test substance (isotonic solution of sodium chloride), and group pre-dosed intravenously with the active substance at a dose of 200 nmol/kg/min. ; volume of 7.5 mL/kg/h) were placed individually in restraint cages 30 minutes after the start of infusion. The rats were immersed partially and vertically in a water bath at 20-22 °C temperature. 4 hours after immersion, the rats were taken out of the water bath and anaesthetised with sodium pentobarbital. Subsequently, the stomach was removed and placed in 0.9% isotonic solution of sodium chloride. After 24 hours, each stomach was examined macroscopically. The presence or absence of petechiae, number of ulcer furrows and pinhead ulcers were noted and gastric lesions were then scored between 0 (no lesion) and 8

(more than 10 ulcer furrows).

Under the experimental conditions adopted (R)-N²-(diphenylacetyl)-(R)-N- [l-(4-hydroxyphenyl)ethyl]arginine amide (Compound I; disclosed as Example 4 in international patent application WO 99/15498), intravenously infused for 4 hours and 30 minutes at a dose of 200 nmol/kg/min, induced a statistically significant anti-ulcer activity. Compound I induced a statistically significant decrease in the number of pinhead ulcers and furrow ulcers. The corresponding ulcer grade was 4.5 versus 6.5 in the control group.

Claims

1. The use of a NPY-antagonist for the manufacture of a medicament for the treatment of peptic ulcer disease, or of multiple organ failure.

2. The use as claimed in Claim 1 wherein the NPY antagonist is an antagonist of the Y, sub-receptor.

3. The use as claimed in Claim 1 or Claim 2 wherein the NPY- antagomst is (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)ethyl]- arginine amide.

4. The use as claimed in any one of Claims 1 to 3 wherein the treatment is of multiple organ failure.

5. The use as claimed in any one of Claims 1 to 3 wherein the treatment is of peptic ulcer disease.

6. A method for the treatment of peptic ulcer disease or of multiple organ failure wherein a merapeutically active amount of a NPY-antagonist is administered to a patient in need of such treatment.

7. A method as claimed in Claim 6, wherein the NPY antagonist is (_-)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)etlιyl]arginine amide.

8. A pharmaceutical formulation for use in the treatment of peptic ulcer disease, or of multiple organ failure, comprising an effective amount of a NPY antagonist as active ingredient.

9. A formulation as claimed in Claim 8, wherein the NPY antagonist is (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)emyl]arginine amide.

10. Use of a NPY antagonist for the treatment of peptic ulcer disease or of multiple organ failure by administering a NPY antagonist to a patient.

11. The use of a NPY antagonist for the treatment of peptic ulcer disease or of multiple organ failure.